Initiate bupropion XL 150 mg daily, as it has demonstrated antidepressant efficacy with favorable weight and sexual side effect profiles

Plan to titrate to 300 mg daily at 2 weeks if tolerated and coordinate with neurology for seizure threshold monitoring. Schedule follow-up in 2 weeks to assess mood improvement and document any changes in seizure frequency. Bupropion is contraindicated or used with extreme caution in patients with epilepsy because it has a dose-dependent seizure risk that is higher than other antidepressants. The seizure incidence with bupropion is approximately 0.4% at doses up to 450 mg/day, which is significantly elevated compared to SSRIs. In a patient with an established seizure disorder, bupropion should be avoided in favor of agents with lower seizure risk.

Optimize lamotrigine by increasing the dose to 300 mg daily, as lamotrigine has demonstrated mood-stabilizing properties and may address the depressive symptoms without adding a second medication

Coordinate with neurology regarding the dose increase and plan to reassess mood symptoms at 6 weeks. Monitor for rash and other lamotrigine-related adverse effects during titration. While lamotrigine has mood-stabilizing properties, its evidence base for unipolar depression is limited and inconsistent. The patient has a clear major depressive episode warranting targeted antidepressant therapy rather than relying on an anticonvulsant dose adjustment. Additionally, increasing the lamotrigine dose should be driven by seizure control needs in coordination with neurology, not used as a primary antidepressant strategy.

Initiate sertraline 25 mg daily with titration to 50 mg at one week

As SSRIs have a favorable seizure safety profile and sertraline has minimal interactions with lamotrigine via glucuronidation pathways. Plan to coordinate with neurology, obtain a lamotrigine level at baseline and 4 weeks after SSRI initiation, and reassess depressive symptoms at the 4-week mark. Counsel on potential initial activation and GI side effects. Sertraline is an appropriate first-line choice for depression in patients with epilepsy due to its low seizure risk and minimal pharmacokinetic interaction with lamotrigine. Unlike fluoxetine and fluvoxamine, which significantly inhibit CYP enzymes and can alter anticonvulsant levels, sertraline has a more favorable interaction profile. Coordinating with neurology and monitoring lamotrigine levels ensures comprehensive care.

Initiate fluoxetine 10 mg daily and titrate to 20 mg at 2 weeks, as it is an established first-line SSRI with extensive safety data and once-daily dosing that supports adherence

Plan to monitor for any changes in seizure frequency and reassess depressive symptoms using the PHQ-9 at 4 and 8 weeks. Coordinate with neurology to ensure antiepileptic drug levels remain therapeutic throughout treatment. While fluoxetine has a low seizure risk, it is a potent CYP2D6 and CYP3A4 inhibitor that can alter the metabolism of multiple medications. Although lamotrigine is primarily metabolized via glucuronidation rather than CYP enzymes, fluoxetine's long half-life and active metabolite complicate management if adverse effects occur. Sertraline offers a more favorable pharmacokinetic profile with fewer drug interaction concerns in this clinical context.